ABSTRACT Carpal tunnel syndrome (CTS) is one of the most widely recognized occupational health conditions. Domestically, the condition affects 3-6% of adults. According to a 2008 report from the Bureau of Labor Statistics, CTS is associated with the second longest average time away from work (28 days) of all major disabling diseases and illnesses in all private industries. The cumulative economic cost is in excess of $2 billion annually, making this the most expensive peripheral neuropathy in the United States. Currently, carpal tunnel release (CTR) surgery is indicated in almost all patients with moderate to severe CTS. CTR surgery involves division of the transverse carpal ligament (TCL). This surgery reduces pressure on the median nerve by increasing the volume of the carpal tunnel. Unfortunately, surgery is invasive and has a large incidence of symptom recurrence and morbidity. Up to 30% of CTR surgery patients report poor to fair strength and long-term discomfort, and 57% have recurrence of some pre-operative symptoms beginning an average of two years after surgery. In recent years, brace-like ligament tensioning devices that attempt to emulate the effects of surgery have emerged, but these devices have had limited success due to the uncomfortable high forces required to manipulate ligament tissues and the lack of compliance due to their obtrusive design. A novel approach to providing long-duration tensioning to carpal tunnel ligaments without reliance on excessive force and/or cumbersome design would be highly desirable as an alternative to CTR surgery. This Phase II SBIR project will continue development of a Carpal Tunnel Tissue Manipulation Device (CTMD) that uses negative pressure to relieve compression on the median nerve without excessive force or cumbersome designs. Unlike the majority of traditional and dynamic splints, the proposed device allows for free movement of the wrist with minimal impediment during daily activities. Our self-funded Phase I efforts involved multiple design iterations until a working prototype was ready for a clinical trial. We then evaluated 4 weeks of CTMD treatment in 11 patients with mild to severe CTS. The study showed that the CTMD reduced CTS symptoms at the end of treatment (4 weeks) and improvement continued or was maintained 2 months after treatment, as determined by the Boston Carpal Tunnel Questionnaire (BCTQ) Symptom Severity Scale (SSS). In this project, the CTMD prototype will be refined to fit more people and will be validated in a larger, longer clinical trial. In Aim 1, PPS will finely tune the design specifications of the CTMD to fit more patients with input from magnetic resonance imaging (MRI) and pressure profile measurements in humans and cadavers. In Aim 2, the new design will be investigated in a 140-subject, multi-site, single-blinded, randomized controlled trial that compares the CTMD to a placebo control. Ultimately, this device could provide a noninvasive, simple and easy-to-use, low-cost alternative to surgery for the millions that suffer from CTS.